Captopril supported on magnetic graphene nitride, a sustainable and green catalyst for one-pot multicomponent synthesis of 2-amino-4H-chromene and 1,2,3,6-tetrahydropyrimidine

Captopril (CAP) is a safe, cost-effective, and environmentally organic compound that can be used as an effective organo-catalyst. Functional groups of captopril make it capable to attach to solid support and acting as promoters in organic transformations. In this work, captopril was attached to the surface of magnetic graphene nitride by employing a linker agent. The synthesized composite efficiently catalyzed two multicomponent reactions including the synthesis of 1,2,3,6-tetrahydropyrimidine and 2-amino-4H-chromene derivatives. A large library of functional targeted products was synthesized in mild reaction conditions. More importantly, this catalyst was stable and magnetically recycled and reused for at least five runs without losing catalytic activity.


Experimental General
All chemicals were purchased from Merck and Sigma Aldrich and used without purification.Electro thermal 9100 apparatus was used to determine of melting points.Sonication for synthesis of catalyst was performed by Elma at 60 Hz.The FT-IR Spectra were detected through Shimadzu IR-470 spectrophotometer.Raman spectroscopy was carried out using a Takram P50C0R10 Raman system.The 1 H and 13 C spectra of products were recorded with a Bruker DRX 400-Avance spectrometer.X-ray diffraction (XRD) pattern was recorded in Philips PW-1830.Magnetic analysis curves were attained by using VSM model MDKB from Danesh Pajohan Kavir Co. Kashan, Iran.The SEM images of the nanocatalyst were recorded via a MIRA 3 TESCAN-XMU instrument.TEM images were recorded with TEM Philips EM-208S, 100 kV.FEI TECNAI F20 instrument was applied for the achievement of high-resolution transmission electron microscopic (HRTEM) images.Elemental analysis of the nanocatalyst (EDS analysis) was done using TESCAN4992 instrument.Thermogravimetric analysis (TGA) was recorded by SDT Q600 V20.9 Build 20 instrument.

Preparation of g-C 3 N 4 nanosheets
According to the reported method 2 .The melamine was heated at 550 °C in a furnace at a ramp of 2.5 °C min −1 in static air for 4 h so bulk g-C 3 N 4 nanosheets powder was synthesized.Then bulk g-C 3 N 4 (1.0 g) was treated in the mixture of 20.0 mL of HNO 3 and 20.0 mL of H 2 SO 4 at room temperature for 2 h.The mixture was diluted with 1.0 L of deionized H 2 O, and the obtained precipitate was filtered and washed several times with deionized water and dried at 60 °C.Then, treated bulk g-C 3 N 4 (1.0 g) was dispersed in 100.0 mL of water/isopropanol (1:1) by sonication for approximately 6 h.Finally, to separate the residual unexfoliated g-C 3 N 4 nanoparticles, the formed suspension was centrifuged (5000 rpm).

Synthesis of Fe 3 O 4 @g-C 3 N 4
Magnetic graphite-like graphitic carbon nitride (g-C 3 N 4 ) was prepared through known reported method 52 .Initially, graphitic carbon nitride (0.4 g) was dispersed in 50 ml deionized water (DI) for 4 h in ultrasonic conditions; then FeCl 3 •6H 2 O (4.68 g, 17.3 mmol) and FeCl 2 •4H 2 O (2.3 g, 18. 14 mmol) were added to the solution.Then, aqueous ammonia solution (15 ml, 25%) was added drop wise to the previous mixture until the pH reached 9-10.The mixture was stirred at 80 ℃ for 2 h under nitrogen atmosphere.The resulting black solid was separated by an external magnet and washed thoroughly with DI water and absolute ethanol, then dried at 50℃ for overnight to provide the Fe 3 O 4 @g-C 3 N 4 .

Synthesis of Fe 3 O 4 @g-C 3 N 4 -PrBr
The resulting Fe 3 O 4 @g-C 3 N 4 (0.5 g) were dispersed in 15.0 mL of dry toluene in ultrasonic conditions then, 1,3-dibromopropane (10 mmol, 1.1 mL) and sodium iodide (0.5 mmol, 0.075 g) was added to the dispersed solution, and the reaction mixture was refluxed overnight under inert atmosphere.The resulted mixture was General procedure for the one-pot synthesis of 1,2,3,6-tetrahydropyrimidine Benzaldehydes (1.2 mmol), EtOH (3 mL), and catalyst (20 mg) were added successively to a stirring mixture of diethyl acetylene dicarboxylate (1.0 mmol) and anilines (2.0 mmol).The mixture was stirred at 50 ℃ for appropriate times.The reaction progress was monitored by TLC.After completion of the reaction, the catalyst was separated, the reaction mixture was diluted with diethyl ether (15 mL) and dried with anhydrous MgSO 4 .Then the mixture was filtered and washed with diethyl ether and the product was purified through recrystallization in ethanol to reach pure products.

Results and discussion
The schematic of catalyst preparation has been illustrated in (Fig. 1) to prepare the Fe 3 O 4 @g-C 3 N 4 nanoparticles, iron salts were added to g-C 3 N 4 prepared from the thermal polymerization of melamine and liquid exfoliation process in flowing (Fig. 1).The presence of functional groups on the Fe 3 O 4 @g-C 3 N 4 , its surface was functionalized with 1,3-dibromopropane as a functionalizing agent to prepare Fe 3 O 4 @g-C 3 N 4 -PrBr.The immobilization of the captopril contains the carboxylic acid group on the magnetic graphitic carbon nitride for the first time is the main novelty of this work (Fe 3 O 4 @g-C 3 N 4 -Pr-Cap) as acidic nanocatalyst.
The FT-IR spectroscopy was employed to characterize the synthesized particles and their modifications.In the spectrum of Fe 3 O 4 @g-C 3 N 4 (Fig. 2a), a broad and strong peak of N-H group and O-H appeared around 2800 − 3600 cm −1 , stretching vibration peaks of C=N were observed at 1637 and 1571 cm −1 , stretching peaks of the C−N heterocycle were at around 1461, 1322, and 1241 cm −1 , and a sharp peak at 810 cm −1 is due to the breathing vibration of tri-s-triazine units.The presence of a strong band at 565-632 cm −1 is related to the Fe-O band in the MNPs.The chemical structure of this intermediate compound, Fe 3 O 4 @g-C 3 N 4 -PrBr, was also confirmed by FT-IR (Fig. 2b).Observation of the main adsorption bands of g-C 3 N 4 indicating the presence of basic g-C 3 N 4 chemical structure.The spectrum of the final composite, Fe 3 O 4 @g-C 3 N 4 -Pr-Cap, is given in (Fig. 2c), the presence of 1690 cm −1 and 1307 cm −1 peaks of C=O and C-O bonds, respectively; approves the existence of captopril in the catalyst.The spectra of modified g-C 3 N 4 also presented O-H and C-H bonds in the structure.
The preparation of the intermediate compound, Fe 3 O 4 @g-C 3 N 4 -PrBr, and the final composite, Fe 3 O 4 @g-C 3 N 4 -Pr-Cap, was also approved by EDS.The EDS spectrum shows the composition of Br atoms in the framework (Fig. 3a) indicating linker attaches to magnetic graphitic carbon nitride.The EDS spectra of the final composite have also been depicted in (Fig. 3b), the existence of the constituent elements of this compound confirmed the formation.
Raman was used to further illustrate the chemical structure of the Fe 3 O 4 @g-C 3 N 4 nanocomposites (Fig. 4).Fe 3 O 4 @g-C 3 N 4 -Pr-Cap showed two main Raman bands at 223 and 652 cm −1 corresponding to vibrational modes of magnetite Fe3O4.In the Raman pattern of g-C 3 N 4 , 704 cm −1 was the typical 3-s-triazine ring breathing vibrational mode peak.Peak at 1325 cm −1 represented the D-band, and peak at 1583 cm −1 represented the G-band.Peak at 1624 and 1696 cm −1 , indicating the presence of C=O groups of the captopril.FE-SEM, TEM, and HR-TEM analysis were applied to study the surface morphology of the catalyst, nano size, uniform distribution, and spherical shape of the particles have been illustrated in (Figs. 5, 6, and 7).Accordingly, the average diameter of nanoparticles was found less than 30 nm.The FE-SEM images obtained indicated wrinkled lamellar structure with relatively smooth surface, suggesting that the surface of Fe 3 O 4 @g-C 3 N 4 sheets were immobilized with captopril.
The thermal behaviour of the prepared composite was investigated using thermogravimetric analysis, and decomposition cures of the final composite and its precursor have been depicted in (Fig. 8).The first weight loss step blew 200 • C , attributed to solvent and water releasing in all samples.The second step of weight loss in the range of 200-597 ℃ comes from the decomposition of organic groups of structures.The thermal stability of the synthesized composite was confirmed by low weight loss at higher temperatures.
The elemental analysis and the percent of weight loss in TGA results were used to calculate the amount of loaded organic species.Captopril is just a source of S in the synthesized composite; therefore, the amount of S (5.08 mmolg −1 , from elemental analysis) was used to find captopril loaded amount (0.75 mmolg −1 ) in harmony with TGA results (0.78 mmolg −1 ).
Vol:.( 1234567890 www.nature.com/scientificreports/ The magnetic properties of Fe 3 O 4 @g-C 3 N 4 and the catalyst were investigated and the values were found as 19.25 emu g −1 and 14.89 emu g −1 , receptively; their related curves are depicted in (Fig. 9).This paramagnetic activity of the catalyst was found to be lower than Fe 3 O 4 @g-C 3 N 4 which may be related to the coating of magnetic graphene nitride with captopril.
The XRD spectrum of the catalyst and its precursor has been presented in (Fig. 10), distinguishing diffraction peaks at 2θ = 30.4°,35.6°, 44.4°, 57.4°, 63.1°, and 74.6° are related to Fe 3 O 4 nanoparticles with cubic phase.Moreover, the presence of conjugated aromatic systems with interplanar stacking crossponding to units g-C 3 N 4 was depicted by existence of diffraction peaks at 2θ = 27.3°.
After synthesis and characterization of the final composite, its catalytic efficiency was investigated in MCR for 2-amino-4H-chromenes synthesis.Initially, the MCR of benzaldehyde, malononitrile, and dimedone was selected as a model for reaction conditions optimization, including the study of the effluence of catalyst amount, the kind of solvent, and reaction temperature on reaction performance.The outcomes are listed in Table 1.
For screening of the catalysts, the reaction was performed in ethanol at 80 °C, without any catalyst, and in the presence of pure magnetic nanoparticles, the reaction was intact (Table 1, entries 1, 4).Employing Fe 3 O 4 @g-C 3 N 4 and Fe 3 O 4 @g-C 3 N 4 -PrBr afforded negligible conversion (Table 1, entries 2, 3).Pure captopril, safe, easily accessible, and low-cost organic compound, exhibited significant efficiency in model reaction (Table 1, entry 5) approved its property; however, considering green chemistry supporting from easy recyclable bed to generation of heterogenous catalyst is a more desirable approach.Interestingly, the magnetic nanoparticle-supported captopril was shown excellent activity in the intended reaction (Table 1, entry 6).After screening the catalyst, the effect of catalyst amount was investigated, more amount of catalysts didn't give better results ( Through the advance of green chemistry, using green media in chemical reactions has been converted into an attractive target in scientific efforts.In this regard, in comparison with flammable and volatile organic solvents, DMF, MeOH, and EtOH are considered safe solvents (Table 1, entries 9, 10).However, among them, EtOH was recognized as a more economical, ecological, and versatile solvent that created suitable reaction conditions to achieve excellent performance, but the application of water and solvent-free media was not succeeded (Table 1,  Optimization reaction conditions in hands, the generality of the catalyst was investigated through the synthesis of several derivatives.The chemical structure of processors, products, and reaction results have been presented in Table 2. Employing several derivatives of benzaldehyde, other components of the reaction keeping the same (Table 2, entries 1-12), with different electronic natures indicating that their electronic properties are not very important points in this reaction, resulting in high reaction yields and short reaction time for all cases.However, replacing dimedone with other diketones led to longer reaction times (Table 2, entries 13-19).As shown in Table 2, in all cases, the products were formed in high to excellent yields (89-97%).In general, our sustainable catalytic system was found as a very active and efficient catalyst for the synthesis of a series of heterocyclic compounds.A gram scale 2-amino-4H-chromene reaction was carried out using optimized reaction conditions.The 2-amino-4H-chromene reaction (Table 2, entrie 5) of benzaldehyde (1.6 g, 15 mmol), malononitrile (1.0 g, 15 mmol), and dimedone (2.1 g, 15 mmol), in presence of EtOH (45 mL) using 0.3 g of the catalyst at 50 °C was conducted.When the scale of the reaction was increased to 15 mmol, the reaction was still found to proceed successfully and the corresponding product was obtained in 90% yield.
The proposed mechanism of the 2-amino-4H-chromene synthesis in the presence of Fe 3 O 4 @g-C 3 N 4 -Pr-Cap has been depicted in (Fig. 11).Captopril supported on magnetic graphene nitride has several acidic catalytic active sites which activate benzaldehyde.Then, malononitrile reacted with the active carbonyl of benzaldehyde, Knoevenagel condensation, Michael addition, and final cyclization leading to the final product.
As a comparison study, the activity of Fe 3 O 4 @g-C 3 N 4 -Pr-Cap has been compared with reported catalytic systems applied for the one-pot multicomponent reaction for 2-amino-4H-chromenes synthesis.The results are listed in Table 3, as can be seen, our catalytic system illustrated high efficiency at extremely short reaction time in desirable mild reaction conditions.
Encouraged by excellent outcomes of 2-amino-4H-chromenes synthesis investigation and optimization reaction conditions in hands (Cat.20 mg, EtOH (3 mL), 50 °C) of the 1,2,3,6-tetrahydropyrimidine derivatives synthesis was performed.Benzaldehydes with diverse electronic properties substituents reacted competently with anilines and diethyl acetylenedicarboxylate, and high yields of products were attained (Table 4).Accordingly, starting materials with different electronic natures did not exhibited any important effect on the reaction yields.
A plausible mechanism of 1,2,3,6-tetrahydropyrimidine synthesis has been given in (Fig. 12).Hydroamination occurred in the first step and amidation was performed in the next step by acid activation assistance.The product was formed in the last step through aldehyde dehydration and cyclization processes.
Difficult separation of homogeneous catalysts is known as a serious problem in chemical transportation due to their economic and environmental disadvantages.In this work, a heterogenous magnetic catalyst was introduced, and after an investigation of its efficiency, its recyclability was studied.For this purpose, after the    www.nature.com/scientificreports/reaction completion, separation of the catalyst from the reaction mixture was done by employing an external magnet bar, washed, and reused in another fresh reaction mixture.The performance of reused catalysts for both studied reactions has been reported in (Fig. 13).The catalyst exhibited significant activity even after five times using.The recycled catalyst was characterized through several analysis methods including XRD, and SEM.The results are reported in (Figs. 14 and 15), these results indicated that no significant changes were observed in comparison with fresh catalyst.
Based on the use of captopril on the catalyst surface and its acidic groups, it leads to spatial congestion with other molecules on the catalyst surface.This spatial congestion can result in the closure of the proximity space around the C-Br bond.It can hinder the interaction of the C-Br bond with other molecules in the reactants, thereby reducing its role.When the catalyst surface is filled with adsorbent groups, the free space for molecular interactions decreases.This can cause congestion and a reduction in interactions involving a specific bond in the reactant molecules.As a result, interactions that rely on that bond for catalytic activity decrease, leading to a diminished role of the C-Br bond in the reaction.Ultimately, the reactive components interact with the free acidic groups in the structure of captopril, promoting reaction progress and high product yield.However, if the reactive components were to react with C-Br instead, it would not result in high product yields.Refer to Tables 2 and 4 to see the yield of the products.In addition to this, the recovered catalyst (Fe 3 O 4 @g-C 3 N 4 -Pr-Cap) was characterized by Energy-dispersive X-ray spectroscopy (EDS) and FT-IR (Figs. 16, and 17).The EDS spectrum displays the    www.nature.com/scientificreports/presence of Br atoms without significant change in comparison with fresh catalyst (Fig. 3b), which is a confirmation that the C-Br bond remains unchanged.The FT-IR of the fresh and recycled catalyst, Fe 3 O 4 @g-C 3 N 4 -Pr-Cap, is given in (Fig. 17).In Fig. 17b, the presence of stretching and bending vibrations of the C−Br at 700 cm −1 and 1100 cm −1 , respectively; approves that C-Br bond remains unchanged.

Conclusion
A magnetically recoverable and green catalyst was developed by immobilizing a safe and sustainable ligand on magnetic graphene nitride.The chemical nature and properties of the catalyst were characterized by different analysis techniques.From the values and the importance of the one-pot multicomponent reaction for the synthesis of heterocycles, we discovered that our environmentally friendly and sustainable catalytic system was super active for the synthesis of a wide-scope of 2-amino-4H-chromenes and 1,2,3,6-tetrahydropyrimidine under mild and green conditions.Moreover, the common problem in these reactions is the formation of unwanted byproducts, which were not formed in the presented synthesis method.The Fe center of the catalyst makes it attractive due to the low cost, availability, and low toxicity of this metal.Magnetic core led to an easy recyclability process; moreover, the catalyst exhibited excellent reusability in at least five reaction runs.\

Ethical approval
This work does not contain any studies with human participants or animals performed by any of the authors. https://doi.org/10.1038/s41598-023-47794-2

Table 2 .
Synthesis of 2-amino-4H-chromene derivatives using the catalyst a . a